MSCs: what’s in a name?

Whether they are "stem" or "stromal", from adult tissues or from umbilical cord blood, MSCs are being used for a lot of clinical trials. Read more

Mopping up immune troublemakers after transplant

Memory CD8+ T cells play an important role in kidney transplant rejection, and they resist drugs that would otherwise improve Read more

Tracking a frameshift through the ribosome

Ribosomal frameshifting, visualized through X-ray Read more

Lynn Marie Trotti

The time Anna stayed up all night

Almost precisely a decade ago, a young Atlanta lawyer named Anna was returning to work, after being treated for an extraordinary sleep disorder. Her story has been told here at Emory and by national media outlets.

Fast forward a decade to Idiopathic Hypersomnia Awareness Week 2018 (September 3-9), organized by Hypersomnolence Australia. What this post deals with is essentially the correction of a date at the tail end of Anna’s story, but one with long-term implications for many people with difficult-to-treat sleep disorders.

In the summer of 2008, Anna Sumner (now Pieschel) was planning on getting back to her life and career. A few years before, she had been diagnosed with a condition with a frustrating name: idiopathic hypersomnia. It means “she sleeps a lot and we don’t know why.”

Neurologist David Rye and nurse practitioner Kathy Parker had treated Anna first with conventional stimulants, which were spectacularly unsatisfactory. See this 2013 Emory Medicine story for details. Parker and Rye eventually landed on something less conventional: flumazenil, an antidote for sedatives that was scarce and difficult to administer. After wrangling with the FDA and with flumazenil’s manufacturer, a longer-term solution came into view. At that time, Anna was unique: the only person taking flumazenil chronically for a sleep disorder.

Then she developed bronchitis. She lost her voice, which was a problem for someone whose professional role sometimes takes her to court. To treat her bronchitis, Anna’s internist had prescribed the antibiotic clarithromycin, known commercially as Biaxin. After taking it, she developed insomnia and couldn’t sleep for three days. She left frantic messages for neurologist Lynn Marie Trotti, who had become her main sleep specialist.

“This had never happened to me before,” she recalled recently. “I was concerned that it was some bizarre individual reaction to the medication.”

In our original Emory Medicine story, this event was described as taking place in 2010. That date was incorrect.  Read more

Posted on by Quinn Eastman in Neuro Leave a comment

Measuring sleepiness: alternatives to five naps

In a 2015 episode of The Simpsons, Homer is diagnosed with narcolepsy. Overwhelming sleepiness at the nuclear power plant lands him in the hospital. Sampling his spinal fluid (ouch!), Homer’s chuckling, deep-voiced doctor quickly performs a test for hypocretin, a brain chemical important for staying awake and regulating REM sleep.

Reality check: testing for hypocretin takes time, and is not currently available in the United States. Let’s talk about how sleep disorders such as narcolepsy and idiopathic hypersomnia are actually diagnosed: operationally, rather than biologically. The less flashy, but standard, way to assess patients is to ask them to take a series of five naps and see how fast they doze off, and how fast they go into REM sleep (the rapid eye movement dreaming phase).

This process, known as the Multiple Sleep Latency Test or MSLT, works pretty well for narcolepsy type 1, the more distinctive form of narcolepsy that includes cataplexy. And it’s hard to fake being sleepy enough to zonk out within a few minutes. But it has a bunch of problems, and dissatisfaction with the MSLT has been developing among sleep specialists for the last several years.

Lynn Marie Trotti, MD

At Emory, neurologists Lynn Marie Trotti and David Rye published an analysis of what I will call the “flip flop problem” in 2013, with others in the field following up more recently. The flip flop problem is: someone who takes the MSLT one day will frequently get another result if they take it again on a different day. Read more

Posted on by Quinn Eastman in Neuro 1 Comment

Post-anesthetic inertia in IH

A recent paper from neurologists Lynn Marie Trotti and Donald Bliwise, with anesthesiologist Paul Garcia, substantiates a phenomenon discussed anecdotally in the idiopathic hypersomnia (IH) community. Let’s call it “post-anesthetic inertia.” People with IH say that undergoing general anesthesia made their sleepiness or disrupted sleep-wake cycles worse, sometimes for days or weeks. This finding is intriguing because it points toward a trigger mechanism for IH. And it pushes anesthesiologists to take IH diagnoses into account when planning patient care, just as is already done for myotonic dystrophy.

Lab Land obtained some confirmation from a couple IHers. One woman had surgery a couple of months ago and felt like the anesthetic was still in her system for weeks and she still didn’t feel right. Another reported “severe insomnia for months and it felt like every body system was completely scrambled.”

Where does this all come from? People with IH getting together and telling their stories. Journalist Virginia Hughes described a moment at the 2014 patient-organized IH meeting in Atlanta in her article “Wake No More”:

Andy Jenkins, the neuroscientist who developed the spinal fluid test, gave an impressively entertaining lecture on GABA receptors. “Why do we have more GABA activity?” somebody asked. Nobody knows, said Jenkins. One idea is that it’s triggered by anesthesia. Lloyd [Johnson, a meeting organizer from Australia] asked the audience how many of them believed their hypersomnia was the result of anesthesia. About one-quarter of the hands went up. “Whoa, whoa, whoa, whoa, whoa,” Jenkins said as he watched the sleepyheads* come alive.

The new paper, in Frontiers in Human Neuroscience, is more quantitative than that informal show of hands. In a way, it begins to question the basis for the term idiopathic hypersomnia, since idiopathic means “arising spontaneously or having no cause”. For some people surveyed in the paper, anesthesia was an exacerbating factor, if not the only factor.

Confusion or agitation post-anesthesia can happen in people who don’t have sleep disorders. What’s peculiar to the hypersomnolent group is how long sleepiness or disrupted sleep-wake cycles last — long after the anesthetic has left the body. The hypersomnolent group was mostly people with IH or narcolepsy type 2 (30 plus 15 out of 57). In the paper, people with restless legs syndrome were used as controls:

While patients in both groups were equally likely to report surgical complications and difficulty awakening from anesthesia, hypersomnolent patients were more likely to report worsened sleepiness (40% of the hypersomnolent group vs. 11% of the RLS group, p = 0.001) and worsening of their sleep disorder symptoms (40% of the hypersomnolent group vs. 9% of the RLS group, p = 0.0001).

Hypersomnolent patients who perceived their symptoms to worsen reported that symptoms had never returned to baseline in 66.7%, took months or years to return to baseline in 9.5%, and resolved in days to weeks in 23.8%.

Note: first author Vincent LaBarbera is now a neurology resident at Brown.

Mechanistic speculation

Several years ago, Emory researchers found that some IH patients appear to have a substance in their cerebrospinal fluid that acts similarly (but not quite the same) as a benzodiazepine drug. This still-mysterious substance enhances signaling by GABA, the major inhibitory neurotransmitter.

Inhaled anesthetics such as sevoflurane, as well as the injected anesthetic propofol, act by enhancing GABA too. So when someone undergoes general anesthesia, their GABA receptors are being pushed hard for an extended period of time. GABA signaling has a kind of global “dimmer switch” function as well as working through specific circuits in the brain to bring on anesthesia.

GABA receptors are complex, but they usually adjust to pressure. It explains development of tolerance to benzodiazepine drugs. GABA receptors also modulate in response to alcohol or women’s menstrual cycles (certain derivatives of progesterone, so-called “neurosteroids,” act on them). What may be happening after anesthesia is that GABA receptors of people with IH have trouble adjusting back, or may overshoot, perhaps because their internal clocks are less resilient.

The Emory authors conclude:

Because the half-life of anesthetic agents is generally short, any prolonged worsening of sleepiness post-procedure cannot easily be attributed to immediate GABA-mediated effects. Whether the putative long-term changes in hypersomnolence that we are detecting in our patients’ reports may be related to changes in GABA-related neural circuitry caused by anesthetic neurotoxicity or other mechanisms remains to be determined.

A similar interaction, with reversed polarity, may be occurring in post-partum depression.

*Lab Land has been told that sleepyhead is not a fully accepted term in the IH community.

Posted on by Quinn Eastman in Neuro Leave a comment

How much does idiopathic hypersomnia overlap with ME/CFS?

In everyday linguistic usage among non-specialists, sleepiness can blend together with tiredness and fatigue. Someone might feel “tired” after climbing a mountain or chopping down a tree, while “sleepiness” is different. Emory sleep scientists explore the pathological distinctions in a paper published in Journal of Sleep Research.

A team led by neurologists Lynn Marie Trotti and David Rye has been studying idiopathic hypersomnia (IH) for several years: people who experience excessive daytime sleepiness and “sleep drunkenness,” not explained by other medical conditions.

IH’s symptoms don’t usually include persistent muscle pain or a severe response to exertion. This separates the disorder from myalgic encephalomyelitis, also known as chronic fatigue syndrome (ME/CFS). But there is some overlap, which is what neurology resident Caroline Maness, Trotti and colleagues report in the new paper. The authors use the official term SEID (systemic exertion intolerance disease), which was recommended by an Institute of Medicine panel in 2015, but hasn’t really stuck among those in the ME/CFS field.

Some people with IH have disclosed that they were previously diagnosed with ME/CFS. Outside of the sleepy vs tired issue, some people with IH report symptoms shared with ME/CFS, such as impaired circulation in their extremities in response to cold, or dizziness upon standing. Speculatively, this may point to a possible problem with the autonomic nervous system. Trotti and a collaborator at Stanford, Mitchell Miglis, are now examining this issue further.

ME/CFS has had a history of controversy. Despite its devastating impacts, some have viewed it as psychological or somehow unreal, and sufferers have felt neglected or maligned by mainstream medicine. The National Institutes of Health has made efforts to turn that situation around by investing in ME/CFS research, and there has been a surge of attention recently covering ME/CFS (Amy Maxmen items in Nature, Stanford magazine feature, Unrest documentary).

Trotti, Maness and colleagues didn’t set out to dive into ME/CFS – they explicitly label this paper a pilot study, and the results say more about the “hypersomnolent” group of patients they have been seeing for the last several years, rather than the broader ME/CFS population. Read more

Posted on by Quinn Eastman in Neuro Leave a comment

Imaging sleep drunkenness: #IHAW2017

At some point, everyone has experienced a temporary groggy feeling after waking up called sleep inertia. Scientists know a lot about sleep inertia already, including how it impairs cognitive and motor abilities, and how it varies with the time of day and type of sleep that precedes it. They even have pictures of how the brain wakes up piece by piece.

People with idiopathic hypersomnia or IH display something that seems stronger, termed “sleep drunkenness,” which can last for hours. Czech neurologist Bedrich Roth, the first to identify IH as something separate from other sleep disorders, proposed sleep drunkenness as IH’s defining characteristic.

Note: Emory readers may recall the young Atlanta lawyer treated for IH by David Rye, Kathy Parker and colleagues several years ago. Our post today is part of IH Awareness Week® 2017.

Sleep drunkenness is what makes IH distinctive in comparison to narcolepsy, especially narcolepsy with cataplexy, whose sufferers tend to fall asleep quickly. Those with full body cataplexy can collapse on the floor in response to emotions such as surprise or amusement. In contrast, people with IH tend not to doze off so suddenly, but they do identify with the statement “Waking up is the hardest thing I do all day.”

At Emory, neurologist Lynn Marie Trotti and colleagues are in the middle of a brain imaging study looking at sleep drunkenness.

“We want to find out if sleep drunkenness in IH is the same as what happens to healthy people with sleep inertia and is more pronounced, or whether it’s something different,” Trotti says. Read more

Posted on by Quinn Eastman in Neuro Leave a comment

Gabbing about GABA — implications for hypersomnia treatments

Anesthesiologist Paul Garcia and his colleagues are presenting two posters at the Society of Neuroscience meeting this week, whose findings may raise concerns about two non-stimulant drugs Emory sleep specialists have studied for the treatment of hypersomnia: flumazenil and clarithromycin.

For both, the data is in vitro only, so caution is in order and more investigation may be needed.

With flumazenil, Garcia and colleagues found that when neurons are exposed to a low dose for 24 hours, the cells increase expression of some GABA receptor forms.

This could be part of a mechanism for tolerance. I heard some anecdotes describing how flumazenil’s wake-promoting effects wear off over time at the Hypersomnia Foundation conference in July, but it’s not clear how common the phenomenon is.

Flumazenil’s utility in hypersomnia became known after the pioneering experience of Anna Sumner, who has reported being able to use the medicine for years. See this 2013 story in Emory Medicine. Read more

Posted on by Quinn Eastman in Neuro Leave a comment

Momentum at hypersomnia conference

A visitor might not realize this was a meeting devoted to people who experience excessive daytime sleepiness. The 2015 Hypersomnia Foundation Conference on Saturday was full of energy, with:

*more than 245 attendees, about twice as many people as last year’s conference

*medical experts from France, Wisconsin and Louisiana — in addition to Emory

*data from several recent clinical trials

*some signs of industry interest in hypersomnia

Hypersomnia is a sleep disorder in which individuals feel frequent or constant sleepiness and need to sleep for long portions of the day (more than 70 hours per week). It is distinct from other sleep disorders such as narcolepsy and sleep apnea, but its prevalence is still unclear. Conventional stimulants such as amphetamine or modafinil often can be used to treat the sleepiness, but some with hypersomnia find these drugs ineffective or hard to tolerate.

Previous research at Emory has shown that many individuals with hypersomnia have a substance in their spinal fluid that acts like a sleeping pill, enhancing the action of the neurotransmitter GABA. The identity of this mysterious substance is unknown, but Emory researchers report that they are close to identifying it. That could give hypersomnia a “molecular handle” similar to what narcolepsy has, with loss of hypocretin-producing neurons.

The terminology is still up in the air — keynote speaker Isabelle Arnulf from Paris said, “The term ‘idiopathic hypersomnia’ does not mean that you are an idiot.” Rather, she said, it means that even specialists can have trouble distinguishing hypersomnia from other sleep disorders, and “idiopathic” signifies that the detailed cause is still under investigation.

Read more

Posted on by Quinn Eastman in Neuro Leave a comment

Hypersomnia update: clarithromycin study

Screen Shot 2015-07-01 at 4.25.58 PM

From Emory Medicine, Spring 2013

A small clinical study of clarithromycin for the sleep disorder hypersomnia shows that the antibiotic can combat patients’ subjective experience of sleepiness, but it does not seem to improve reaction time measured in a video-game-type vigilance task.

The effects of clarithromycin in hypersomnia were first observed by Emory doctors when a pioneering patient (Anna Sumner, whose story is told in this Emory Medicine article) unexpectedly experienced sleeplessness when taking it for a respiratory infection.

The results of the study were published online by Annals of Neurology on June 10.

Lynn Marie Trotti, MD, David Rye, MD, PhD and colleagues from the Department of Neurology and Emory Sleep Center conducted the study, which involved 23 patients.

Advantages of clarithromycin:

  1. It’s inexpensive and widely available.
  2. It’s an option for people dealing with hypersomnia for whom other medications, such as modafinil, are not helpful or tolerable.
  3. It represents an alternative to flumazenil, the benzodiazepine antidote that has been shown to help some hypersomnia patients. Flumazenil used to be very scarce, and shortages occur (Hypersomnia Foundation/American Society of Health System Pharmacists).

Disadvantages of clarithromycin:

  1. It’s an antibiotic, so it probably changes intestinal bacteria.
  2. Chronic use could promote the growth of antibiotic-resistant bacteria.
  3. Most patients reported an altered sense of taste or smell. Some describe this as a metallic mouth sensation.

Read more

Posted on by Quinn Eastman in Neuro Leave a comment